Rat transcriptome biomarkers for the prediction of temporal lobe epilepsy

描述(申请人提供)：癫痫持续状态(SE)是海马神经变性和突触重组的常见原因，最终可能导致或可能不导致颞叶癫痫(TLE)的发展。虽然SE作为TLE的可能原因已经被认识到，但目前还没有有效的预后工具来可靠地预测SE后患者是否真的会发展成慢性癫痫。因此，SE后患者是否应该接受抗癫痫预防性治疗尚不清楚，在这种情况下，这种治疗的有效性也很难评估。该提案的目的是应用基于微阵列的方法来分析颞叶癫痫大鼠模型血液中的表达变化，以确定TLE的新的和预后的外周生物标志物。这将通过比较和鉴定实验动物外周血中常见的基因组变化来实现，尽管动物的品系、年龄、性别和SE模型是常见的。雄性和雌性Wistar和Spraogue-Dawley大鼠在儿童期(出生后35天)或成年(出生后90天)接受全身毛果芸香碱或海人藻氨酸诱导的SE。SE后1天、3天和7天采集外周血样本，进行基因组分析。SE后，将使用脑电和视频对动物进行持续监测，以了解自发性复发边缘癫痫的发生、频率和严重程度，为期六周。癫痫综合征将与血液基因组图谱的变化追溯相关。如果成功，我们的研究将允许对那些在TLE发生之前以特定方式改变其表达的基因进行大规模的平行、经济有效的表达分析。该项目将产生一种定制的TLE预后生物标志物芯片，可用于筛查和诊断潜在的TLE患者，并前瞻性地评估抗癫痫治疗的效果。 项目简介：无论是全身匹罗卡品还是海马内注射，红藻氨酸都是一种急性神经系统疾病，由一段持续的长时间癫痫发作组成。SE后，相当一部分患者发展为慢性癫痫。目前还没有能够预测SE后患者是否会出现癫痫的诊断工具。目前的项目建议开发一种简单的诊断性血液测试方法，该方法可以预测SE后患者癫痫的发展。这项测试将基于检测癫痫进展之前外周血中特有的基因表达变化。这将提供一个重要的诊断工具，并可能表明预防性治疗的必要性，以防止慢性癫痫的发展和进展。这样的测试在抗癫痫治疗效果的预后评估中也是有用的。

DESCRIPTION (provided by applicant): Status epilepticus (SE) is a common cause of hippocampal neurodegeneration and synaptic reorganization that ultimately may, or may not lead to the development of temporal lobe epilepsy (TLE). While the role of SE as a possible cause of TLE has been recognized, no effective prognostic tools exist that would reliably predict whether chronic epilepsy would indeed develop in post-SE patients. Hence it is not known whether post- SE patients should undergo antiepileptogenic preventive therapy, and in which case, the effectiveness of such therapy is difficult to assess. The goal of this proposal is to identify novel and prognostic peripheral biomarkers of TLE applying a microarray-based approach for the analysis of expression changes in the blood of rat models of temporal lobe epilepsy. This will be achieved through comparison and identification of genomic changes in peripheral blood of experimental animals that are common despite animal strain, age, sex, and SE model. Male and female Wistar and Sprague-Dawley rats will be subjected to SE induced by either systemic pilocarpine or intrahippocampal kainic acid during either childhood (postnatal day 35) or adulthood (postnatal day 90). Samples of peripheral blood collected one, three and seven days after SE, will undergo genomic assay. After SE, animals will be continuously monitored using both EEG and video for the occurrence, frequency and severity of spontaneous recurrent limbic seizures for a period of six weeks. Seizure syndrome will be retrospectively correlated with the changes in blood genomic profile. If successful, our study would allow a large-scale parallel, cost-effective expression analysis of genes whose expression is altered in a specific fashion prior to the development of TLE. The project will generate a custom TLE prognostic biomarker chip that can be used both to screen and diagnose potential TLE patients, and to prospectively evaluate the effectiveness of antiepileptogenic therapy. Project narrative: by either systemic pilocarpine or intrahippocampal kainic acid is an acute neurological condition that consists of an episode of long-lasting continuous seizure. After SE, significant portion of patients develop chronic epilepsy. Currently no diagnostic tools exist that would allow predicting whether post-SE patient would develop epilepsy. The current project proposes the development of a simple diagnostic blood test method that would allow predicting the development of epilepsy in post-SE patients. The test will be based on the detection of characteristic gene expression changes in the peripheral blood that precede the progression of epilepsy. This will provide an important diagnostic tool and could indicate the necessity of prophylactic treatment to prevent the development and progression of chronic epilepsy. Such a test would also be useful in prognostic assessment of the effectiveness of antiepileptic therapy.